The major objective of the proposed research will be to clarify the anatomic characteristics and significance of the myocardial lesions that occur in the shock syndrome. In previous studies we have demonstrated 2 types of lesions: 1) subendocardial hemorrhage and necrosis (SEHN), and 2) zonal lesions. Both have been shown to be related to effects of increased catecholamines in shock, the first type (SEHN) being caused by anoxia, and t e zonal lesions not being caused by anoxia. One approach of the present project will be to attempt to demonstrate a "no reflow" effect in the subendocardial region of dogs subjected to experimental hemorrhagic shock, and then to determine the effect of hypertonic mannitol treatment in preventing the "no reflow" effect as well as the SEHN. Another approach to the prevention of the subendocardial ischemic necrosis will be to combine treatment with a beta sympathetic blocking agent (to "rest" the heart) with intra-aortic balloon pumping (to support the circulation). In order to clarify the nature of zonal lesions, the conditions leading to their formation will be simulated in vitro using a cat papillary muscle preparation, in which the various factors can be dissected out (e.g. heart rate, increased catecholamines, alteration in calcium and magnesium concentration, increased lactate concentration). The conditions leading to zonal lesion formation will also be sought in patients who die shortly after cardio-pulmonary bypass surgery, in which situation we have demonstrated that zonal lesions may occur. In all of these studies light and electron microscopic and histochemical techniques will be utilized. It is hoped that better understanding of the mechanisms of lesion formation in shock will contribute to our basic knowledge of cardiac injury in general, and could lead to more rational prophylactic and therapeutic approaches to the irreversibility problem in human shock.